Approximately 10% of women in Western populations experience early natural menopause, defined as menopause before age 45. Early menopause can significantly impact women's psychological and physical health, as the early cessation of ovarian function influences fertility and family planning, and increases risk of cardiovascular disease, osteoporosis and other chronic conditions. The ability to identify women at risk for early menopause prior to the onset of decline in reproductive function would improve options for treatment and prevention. Accurate prediction of early menopause is dependent upon the identification of all biochemical, reproductive, dietary and lifestyle factors that are importantly associated with risk. Large prospective studies evaluating multiple risk factors simultaneously are needed, but few have been conducted. Finding from these studies can not only improve clinical prediction but can provide insight into whether risk of early menopause is modifiable and declines in reproductive function in high-risk women can be slowed. We propose to determine how biochemical, reproductive, dietary and lifestyle factors are related to risk of early menopause among members of the Nurses' Health Study II (NHS2), an ongoing prospective study of 116,000 women, aged 25-42 at cohort inception in 1989. Early menopause was experienced by more than 3,500 NHS2 participants over 24 years of follow-up, including 500 women who provided a blood sample up to 15 years prior to menopause. In this project, we will first evaluate whether anti-Mllerian hormone (AMH) predicts risk of early menopause, comparing levels in 500 women with early natural menopause to levels in 500 matched controls with menopause at e age 48. Second, we will expand knowledge of the etiology of early menopause by evaluating prospectively how risk is related to the following: 1) inflammation markers including C-reactive protein, interleukin-6, and tumor necrosis factor alpha receptor 2 levels; 2) total and bioavailable 25- hydroxyvitamin D levels; and 3) reproductive, dietary and lifestyle factors. Third, we will determine whether biochemical and behavioral factors are themselves associated with baseline AMH levels and rate of AMH decline over 10-14 years. Finally, we will develop prediction and etiologic models for early menopause that incorporate all of this information. Our study in the NHS2 will be among the first to evaluate prospectively how biochemical, reproductive, dietary and lifestyle factors collectively relate to early menopause. To our knowledge, it will be the first to investigate whether vitamin D and inflammatory factors are associated with risk of early menopause, and among the first to address whether women at high risk for early menopause may be able to slow early decline in reproductive function. This work is an important first step in developing novel interventions, which can then be tested in clinical trials. Results from this study may have important implications for fertility preservation and for improved prevention of cardiovascular disease and other chronic conditions in at-risk women.